Process for preparing spray granules containing riboflavin

ABSTRACT

The invention is concerned with a novel process for the manufacture of flowable, non-dusty, binder-free riboflavin granulates by subjecting an aqueous suspension of riboflavin crystals of crystal modification B/C to a fluidized bed spray drying process, a single fluid nozzle spray drying process or a disk-type spray drying process.

FIELD OF THE INVENTION

The present invention is concerned with a novel process for themanufacture of flowable, non-dusty, and binder-free riboflavingranulates.

BACKGROUND OF THE INVENTION

Riboflavin granulates can be produced, for example, by a compactingprocess. European publication EP 0 414 115 BI describes a compactingprocess in which riboflavin powder with an average particle diametersmaller than 25 μm is pressed to strands. A comminution procedurefollows the pressing operation to give riboflavin granulates having anaverage particle diameter of 50 μm to 1000 μm.

European publication EP 0 457 075 B1 describes a process for theproduction of flowable, non-dusty, and binder-free riboflavin granulateswith a particle size of 50 μm to 450 μm from finely divided riboflavin.The process subjects an aqueous suspension or a suspension containing atleast 10 wt. % water, which contains at least 5 to 30 wt. % of pureriboflavin, to a fluidized bed spray drying process that uses a singlefluid nozzle spray drying process or a disk-type spray drying process attemperatures of 20 to 100° C. without adding a binder to the suspension.The riboflavin is produced by simply spray drying an aqueous suspensionof riboflavin or by rapid precipitation from acidified, aqueousriboflavin solutions at temperatures below 50° C. or by rapidprecipitation and rapid cooling of hot, aqueous riboflavin solutions ata pH value between 0.8 and 6.5. The crystal form of the riboflavin usedis not disclosed. It is, however, generally known that the riboflavinproduction described in EP 0 457 075 B1 leads to riboflavin of crystalmodification A.

A process for the production of dendritic riboflavin crystals isdescribed in European Patent Application 98119686.8. This processinvolves pre-purification, crystallization, and drying. Needle-shapedriboflavin of stable modification A is dissolved in an aqueous mineralacid solution at about 30° C. and active charcoal is added to theresulting solution in order to adsorb impurities present in thesolution. Thereafter, the medium containing the active charcoal issubjected to a cross-flow filtration over a ceramic membrane having apore size of about 20 nm to about 200 nm. The five- to ten-fold amount(vol./vol.) of water is added to the resulting filtrate at about 30° C.The precipitated, spherical riboflavin crystals are separated bycentrifugation or filtration.

If desired, the riboflavin crystals can be washed with water andsubsequently dried according to methods known per se.

DETAILED DESCRIPTION OF THE INVENTION

The starting material used is needle-shaped riboflavin of modification Aas is found, for example, in the production of foodstuffs. Thisriboflavin has a content of about 85 wt. % to about 98% of pureriboflavin. Varying amounts of chemical byproducts and/or fermentationresidues, as well as water, are present depending on the route ofproduction.

In the first stage of the process, needle-shaped riboflavin ofmodification A in dry or filter-moist form is dissolved in the aqueousmineral acid. The dissolution takes place by a protonation reaction. Inthe dissolution procedure, fermentation residues, such as proteins,peptides, amino acids, and/or chemical byproducts become liberated andare then present partly in solution and partly in solid form. As themineral acid, there is especially suitable hydrochloric acid or nitricacid, the concentration of which is about 10 wt. % to about 65 wt. %. 18wt. % to 24 wt. % hydrochloric acid is especially preferred. Up to about19 wt. % dry riboflavin is dissolved in such an aqueous hydrochloricacid solution. The solution is thus almost saturated. The dissolutionprocedure is effected at temperatures up to a maximum of 30° C., usuallyat about 5 to about 25° C., preferably at about 10 to about 20° C.,conveniently with intensive intermixing, for example by intensivestirring. The dissolution time can be reduced by increasing thetemperature and/or intensifing the intermixing. The overall dissolutionprocedure usually takes up to about 30 minutes depending on thetemperature and intermixing.

In the next stage of the process, active charcoal is added to thesolution of the riboflavin in the aqueous mineral acid solution.Thereby, the impurities present in the solution are adsorbed on theactive charcoal. The active charcoal can be pulverized or granulated.Conveniently, about 0.5 to about 9 wt. %, preferably about 3 wt. %, ofactive charcoal based on the riboflavin content is added. Depending onthe impurities, the active charcoal is left in the solution for up toabout 12 hours, preferably about 0.5 to about 3 hours. Acid-washedactive charcoal with a bulk density of about 250 to about 400 kg/m³,preferably about 300 kg/m³, a specific surface area of about 1200 toabout 1600 m²/g, preferably about 1400 m²/g, and an average particlesize of about 20 to about 70 μm is suitable as the active charcoal.Examples of suitable active charcoals are Norit CA1 and Bentonorit,which are especially suitable for the adsorption biological impurities,as well as Norit SX 2, which in turn is especially suitable for theseparation of chemical impurities.

In addition to the active charcoal there can be added to the aqueousmineral acid solution a filter aid, of which conveniently about 2 toabout 9 wt. % based on the riboflavin content are used. Suitable filteraids are, for example, cellulose, such as Arbocel BWW 40 and B 800 fromthe company Rettenmaier & Söhne GmbH+Co.

The separation of the active charcoal, the filter aid, which may bepresent, and the undissolved fermentation residues present is effectedby the subsequent cross-flow filtration. In addition to the adsorption,the active charcoal also has an abrasive action on the covering layerwhich forms the membrane. By this action, it is now possible to operatethe membrane in a stable manner over a longer period of time with almostdouble the throughput than without active charcoal. The active charcoalthus possesses not only abrasive, but also adsorptive properties. Thecross-flow filtration is effected over a ceramic membrane, which has apore size of about 20 to about 200 nm, preferably of about 50 nm. Theactive charcoal pumped around in the circuit brings about by theabrasion a cleansing of the covering layer of carbon and fermentationresidues formed on the membrane. As a rule, the counter-current velocityover the membrane is relatively high; it conveniently lies in the regionof about 5 to about 6 m/s. In order not to compress the covering layerexcessively, the trans-membrane pressure is conveniently1 to 2 bar (0.1to 0.2 MPa).

After the cross-flow filtration, the solution of riboflavin, which isalmost free from all impurities, the active charcoal, as well as filteraid, which may be present, is brought to crystallization, which iseffected by the addition of a five- to ten-fold amount of water. Thedeprotonization of the riboflavin present in the aqueous mineral acidsolution, which thereby takes place, leads to its precipitation.

The temperature of the medium in which the crystallization takes placecan be varied in a range of 0 to 30° C. depending on the productionmethod and impurity grade of the riboflavin. Especially in the case ofsynthetically produced material, the temperature can be increased to 30°C.; in the case of fermentative or relatively clean materialtemperatures below 10° C. are generally preferred. Most preferred is atemperature between 4 and 10° C. The crystallization can be carried outbatchwise or continuously, preferably continuously. Cascades orindividual kettles can be used as the crystallizer. Especially in thecase of individual kettles, it is advisable to feed in at differentpositions in the kettle. Within the crystallizer, a very goodmacroscopic intermixing must be set up in every case. This can berealized, for example, by using a two-stage stirring device, with thefeed solutions displaced by 180° being fed on to the upper and lowerstirrer levels. Conveniently, in so doing, water is added to the upperlevel and the mineral acid solution of the riboflavin is added to thelower level. The stirring should be carried out very carefully in ordernot to damage the crystals. The residence time suitably varies betweenabout 5 and about 20 minutes, preferably about 10-13 minutes. Thesubsequent filtration is effected using a filter or a centrifuge, whichis very efficient. Preferably a band filter is used on which the washingmay also be carried out. The drying can be carried out in a manner knownper se.

The initial relative supersaturation in the crystallizer (prior to theaddition of water) can be regulated by recycling the mother liquor aswell as by water flowing into the crystallizer. The mother liquor:waterratio is conveniently about 1:1 to about 1:8. The relativesupersaturation can be estimated via the conductivity present in thecrystallizer, with a range of about 170 to about 200 mS/cm ideally beingadhered to. The recycling of the mother liquor can be terminateddepending on the conductivity. In the case of the recycling, it ispreferably regulated via the conductivity existing in the crystallizer.

By a suitable choice of mixing ratio, temperature, and residence time,it is possible to crystallize an unstable modification of riboflavin,with the particles being spherical with a spiky surface and, thus,having a substantially larger surface area than the known needle-shapedcrystals of modification A. The spherical crystal does not result by anagglomeration procedure as has hitherto been generally described in theliterature for spherical crystals [see, for example, European Patent 0307 767 B1 and Can. J. Chem. Eng. 47, 166-170 (1969)]; on the contrary,in the case of the new process, needle-shaped crystals grow from aninitially crystallized-out, small, probably amorphous seed. Thethus-obtained dendritic crystals correspond to the more solublemodifications B and, respectively, C, which have an adequate storagestability and, furthermore, by virtue of the unstable modification andlarger surface area, have outstanding dissolution properties.

As mentioned above, the crystallizate is separated by filtration orcentrifugation. The filter cake is washed with water. Subsequently, themoist filter cake can be dried.

The thus-produced dendritic crystals are a mixture of crystalmodifications B and C, which are more unstable compared withmodification A.

It has now surprisingly been found that flowable, non-dusty, andbinder-free riboflavin granulates can be manufactured from a mixture ofriboflavin crystals of modification B and C, which has been producedaccording to the process described above. The crystal modifications Band, respectively, C thereby do not revert back to the more thermostableneedle-shaped crystal modification A.

The object of the invention is therefore a process for the manufactureof that flowable, non-dusty, and binder-free riboflavin granulates,which process comprises subjecting an aqueous suspension of riboflavincrystals of crystal modification B/C to a fluidized bed spray dryingprocess, a single fluid nozzle spray drying process, or a disk-typespray drying process.

In the scope of the present invention the term “riboflavin crystals ofcrystal modification B/C” embraces riboflavin crystals as obtainedaccording to the process described above. Dried crystals exhibit crystalmodification B. In the moist state a mixture of crystals of modificationB and C is present.

In the scope of the present invention the term “fluidized bed spraydrying process”, “single fluid nozzle spray drying process” or“disk-type spray drying process” embraces processes as described inEuropean Patent EP 0 457 075 B1 and U.S. Pat. No. 5,300,303,respectively, which are herein incorporated by reference. The preferreddrying process is a single fluid nozzle spray drying process.

The riboflavin is used in the form of an aqueous suspension. Thesuspension has a riboflavin content of about 5 wt. % to about 25 wt. %,preferably of about 9 wt. % to about 12 wt. %.

For the performance of the single fluid nozzle spray drying process,there is used a centrifugal-pressure nozzle as supplied, for example, bythe company Schlick or by the company Spraying Systems. However, othercentrifugal-pressure nozzles are also suitable.

The aqueous riboflavin suspension is sprayed into a drying tower bymeans of a centriftigal-pressure nozzle. The spraying pressure is up to150 bar, preferably about 15 bar to about 40 bar.

The temperature of the drying gas is about 150° C. to about 240° C.,preferably about 170° C. to about 200° C., at the entrance of the dryingtower and about 70° C. to about 150° C., preferably about 80° C. toabout 110° C., at the exit of the drying tower.

The riboflavin granulate obtained according to the process in accordancewith the invention consists of particles with a particle size of about20 μm to about 400 μm.

The surface structure of the spray-dried particles is spherical withfolds and differs significantly from the surface structure ofspray-dried particles from riboflavin of crystal modification A, whichhave a spherical smooth surface.

The spray granulate obtained according to the process in accordance withthe invention surprisingly has the following advantages vis-à-vis theknown riboflavin granulates of crystal modification A:

The riboflavin granulate has very good compression properties. Theresults will be evident from Tables 4 and 6.

Upon dissolution of the granulate in water, the riboflavin of crystalmodification B shows a high solubility in comparison to riboflavin ofcrystal modification A. Solutions are obtained with a riboflavinconcentration greater than 15 mg riboflavin/100 ml water, preferablygreater than 16 mg riboflavin/100 ml water, more preferably about 16 mgriboflavin/100 ml water to about 18 mg riboflavin/100 ml water. When thegranulate is dissolved in 0.1N HCl, solutions of about 18 mgriboflavin/100 ml 0.1N HCl to about 20 mg riboflavin/100 ml 0.1N HCl areobtained. The results are reproduced in Table 2.

Upon dissolution of a tablet that has been pressed from riboflavingranulates in accordance with the invention, a high solubility of theriboflavin of crystal modification B is observed. About 98 wt. % of theriboflavin has passed into solution after 45 minutes compared with 47wt.% when using a riboflavin granulate from riboflavin of crystalmodification A.

The riboflavin particles have a good mechanical stability, although nobinder is added.

The riboflavin particles have a good chemical stability. The goodstability remains even after storage at a high temperature.

EXAMPLES

The invention is illustrated on the basis of the following Examples:

Examples 1-3 relate to the production of a mixture of riboflavincrystals of crystal modification B and C.

Examples 4-6 describe riboflavin granulates in accordance with theinvention.

Example 7 is a comparative Example.

Examples 8 and 9 describe the production of a tablet.

Example 1

The starting material used for the process described hereinafter wasfermentatively produced riboflavin, which had a riboflavin content of97.02% (according to HPLC), a residual moisture content (H₂O) of 0.80%,as well as an amino acid content of 1.11% and was present asneedle-shaped crystals of the stable modification A.

350.0 g of this starting material were dissolved in 1708.6 g of 24%hydrochloric acid at 22° C. while stirring. After a dissolution periodof about 15-20 minutes, a brown-black solution containing about 17% ofriboflavin was present.

16 g (about 3% of the amount of riboflavin) of active charcoal (Norit®CA1) were subsequently added to the solution and the mixture was stirredfor a further 4 hours. The mixture was filled into the double-jacketedfeed tank of a laboratory membrane apparatus. The tank was cooled inorder to maintain a maximum temperature of 35° C. Using a centrifugalpump the solution was pumped over a ceramic membrane with an effectivesurface area of 0.0055 m². The trans-membrane pressure was adjusted to1.5 bar (0.15 MPa) and the cross-flow velocity over the membrane wasadjusted to 6 m/s. This gave a permeate throughput of about 100 l/m²/h,which could be maintained almost to the end of the filtration.

The hydrochloric acidic riboflavin solution was then crystallized in acontinuously operating precipitation crystallizer.

The 3 l precipitation crystallizer was firstly filled with about 2 l ofwater and the liquid was stirred at 100 rpm with a two-stage inclinedflat blade paddle stirrer and subsequently cooled to 10° C. Thereafter,at about 10° C., simultaneously and continuously, 1590 g/h ofhydrochloric acidic riboflavin solution were dosed in at the upperstirrer and about 9000 g/h of water were dosed in at the lower stirrer.About 2-4 minutes after the start the riboflavin began to crystallizeout as orange-yellow crystals. Initially, the separated crystalsappeared to be flocculent, but after 20-30 minutes they changed intogranular particles. The crystal suspension was then drained offcontinuously until in the crystallizer the 3 l mark (double jacket end)had been reached (i.e., after about 7 minutes). The valve was adjustedso that the level settled down at the 3 l mark. The dischargedsuspension was added directly to a P3 suction filter and there the solidwas separated from the solution.

About 2500 ml of suspension were collected every 15 minutes and a filtercake about 1 cm thick was obtained. This was then washed in portionswith 1300 ml of water until a pH of about 5 had been reached.

The moist, yellow crystallizate (65-75% residual moisture) wassubsequently dried. Dried crystals exhibit crystal modification B.

Example 2

A riboflavin solution was produced and treated with active charcoal asdescribed in Example 1. In contrast to Example 1, the solution waspurified over a membrane having a pore size of about 50 nm. Thetrans-membrane pressure lay at 1.5 to 1.7 bar (0.15 to 0.17 MPa) and thecross-flow velocity lay at 5 to 6 m/s. This gave a permeate throughputof about 70 l/m²/h. The crystallization, filtration and washing werecarried out analogously to Example 1. The crystallization temperaturelay between 9 and 10° C. and the drying was carried out in a laboratorydrying oven at 100° C.

Dried crystals exhibit crystal modification B.

Example 3

The starting material used was chemically produced riboflavin having acontent of 98%. The starting material was dissolved as described inExample 1. The cross-flow filtration was carried out as described inExample 2. The crystallization was carried out at 20° C. and by dosingin 1030 g/h of hydrochloric acidic riboflavin solution and 15060 g/h ofwater. Filtration and washing were carried out analogously to Example 2.The drying was carried out analogously to Example 2.

The results of the above three Examples are compiled in Table1hereinafter. Dried crystals exhibit crystal modification B.

TABLE 1 Modification (according to Riboflavin Lumichrome LumiflavinX-ray content content content Amino Exam- structural according accordingaccording acid ple analysis) to HPLC to HPLC to HPLC content 1 B   98%0.08% —  0.1% 2 B 98.9% 0.15% — 0.06% 3 B   99% 0.15% 0.25% —

The respective missing percentage number comprises the water content andother small impurities.

Example 4

The filter cake from Example 1 was diluted with water to give asuspension with a riboflavin content of 9.3 wt. %.

Example 5

The filter cake from Example 1 was diluted with water to give asuspension with a riboflavin content of 11.4 wt. %.

Example 6

The filter cake from Example 1 was diluted with water to give asuspension with a riboflavin content of 11.1 wt. %.

Example 7

Synthetically produced, commercial riboflavin of modification A wasdiluted with water to give a suspension with a riboflavin content of32.0 wt. %. There were obtained very unstable particles whichdisintegrated to dust with low mechanical load and accordingly did nothave the desired product properties.

The suspensions of Examples 4-7 were sprayed into a drying tower bymeans of a centrifugal-pressure nozzle. Table 2 hereinafter shows theprocess parameters and the improvement in the solubility of theriboflavin from the riboflavin granulates in accordance with theinvention compared with known riboflavin granulate from riboflavin ofcrystal modification A.

TABLE 2 Example 4 5 6 7 Crystal modification B/C B/C B/C A Added amountof riboflavin 56 41 56 103 suspension in kg/h Dry substance ofriboflavin 9.3 11.4 11.1 32.0 suspension in % Temperature of riboflavin22 27 22 14 suspension in ° C. Spraying pressure in bar 20 21 15 29Amount of drying air in kg/h 2500 1670 1851 1797 Air inlet temperature,° C. 180 165 200 190 Air outlet temperature in ° C. 115 97 106 110Riboflavin solubility in mg/100 ml 17.3 17.7 16.3 8.4 water Riboflavinsolubility in mg/100 ml 19.2 19.6 18.4 10.1 0.1 N HCl Riboflavinsolubility in mg/100 ml 17.7 17.7 15.6 9.2 water after storage for 9months in a polyethylene bottle at 45° C./ 75% relative humidityRiboflavin solubility in mg/100 ml 18.9 18.4 18.1 10.0 0.1 N HCl afterstorage for 9 months in a polyethylene bottle at 45° C./ 75% relativehumidity

Example 8

Tablets that contained about 100 mg of riboflavin were produced in aknown manner according to the direct tabletting process. The suspensionsdescribed in Examples 4-7 were used. Table 3 hereinafter shows thecomposition of the tablets.

TABLE 3 Riboflavin according to 110 mg Example 4, 5 and 6 Riboflavin 98%tlc according 112.2 mg to Example 7 Avicel pH 102 10.7 mg 10.7 mgPolyplasdone XL 8.3 mg 8.3 mg Magnesium stearate 1.0 mg 1.0 mg Total130.0 mg 132.2 mg

Table 4 hereinafter shows the improved compression properties ofriboflavin granulates from riboflavin of crystal modification Bvis-à-vis known riboflavin granulate from riboflavin of crystalmodification A.

TABLE 4 Riboflavin according to Example 4 5 6 7 Compression force 700 kp700 kp 700 kp 700 kp Hardness 195 N 191 N 207 N 159 N

Example 9

Tablets that contained about 150 mg of riboflavin were produced in aknown manner according to the direct tabletting process. The suspensionsdescribed in Examples 4-7 were used. Table 5 hereinafter shows thecomposition of the tablets.

TABLE 5 Riboflavin according to 165 mg Example 4, 5 and 6 Riboflavin 98%tlc according 168.4 mg to Example 7 Avicel pH 102 11.0 mg 11.2 mgPolyplasdone XL 3.0 mg 3.07 mg Magnesium stearate 1.0 mg 1.03 mg Total180.0 mg 183.7 mg

Table 6 hereinafter shows the improved compression properties ofriboflavin granulates 5 from riboflavin of crystal modification Bvis-à-vis known riboflavin granulate from riboflavin of crystalmodification A.

TABLE 6 Riboflavin according to Example 4 5 6 7 Compression force 500 kp500 kp 500 kp 500 kp Hardness 194 N 207 N 176 N 76 N Compression force800 kp 800 kp 800 kp 800 kp Hardness 199 KN 233 N 225 N 115 NCompression force 1000 kp 1000 kp 1000 kp 1000 kp Hardness 254 N 268 N244 N 146 N

The improved water solubility of riboflavin granulates from riboflavinof crystal modification B vis-à-vis known riboflavin granulate ofcrystal modification A can be determined in the “USP Dissolution Test.”In the case of the product in accordance with the invention 98% to 100%of the riboflavin present in the tablets had dissolved after 45 minutes,while when tablets which contained riboflavin of crystal modification Awere used only 47% of the riboflavin present in the tablets haddissolved.

While the invention has been illustrated and described with respect toillustrative embodiments and modes of practice, it will be apparent tothose skilled in the art that various modifications and improvements maybe made without departing from the scope and spirit of the invention.Accordingly, the invention is not to be limited by the illustrativeembodiments and modes of practice.

What is claimed is:
 1. A process for the manufacture of flowable,non-dusty, and binder-free riboflavin granulates, which processcomprises drying an aqueous riboflavin crystal suspension of crystalmodification B/C by a process selected from the group consisting of afluidized bed spray drying process, a single fluid nozzle spray dryingprocess, and a disk-type spray drying process.
 2. A process inaccordance with claim 1, wherein the drying process is a fluidized bedspray drying process.
 3. A process in accordance with claim 1, whereinthe drying process is a single fluid nozzle spray drying process.
 4. Aprocess in accordance with claim 1, wherein the drying process is adisk-type spray drying process.
 5. A process in accordance with claim 1,wherein the aqueous suspension has a riboflavin content of about 5 wt. %to about 25 wt. %.
 6. A process in accordance with claim 5, wherein theriboflavin content is about 9 wt. % to about 12 wt. %.
 7. A process inaccordance with claim 1, wherein a centrifugal-pressure nozzle spraysthe aqueous suspension into a drying tower at a spray pressure up to 150bar.
 8. A process in accordance with claim 7, wherein the spray pressureis about 15 bar to about 40 bar.
 9. A process in accordance with claim7, wherein the drying gas temperature at the entrance of the dryingtower is about 150° C. to about 240° C.
 10. A process in accordance withclaim 9, wherein the temperature is about 170° C. to about 200° C.
 11. Aprocess in accordance with claim 7, wherein the drying gas temperatureat the exit of the drying tower is about 70° C. to about 150° C.
 12. Aprocess in accordance with claim 11, wherein the temperature is about80° C. to about 110° C.
 13. A riboflavin granulate obtained by a processin accordance with claim
 1. 14. A riboflavin granulate in accordancewith claim 13, having particles with a particle size of about 20 μm toabout 400 μm.
 15. A process for producing an aqueous riboflavin solutioncomprising dissolving a riboflavin granulate of claim 13 in water toform a solution having a riboflavin concentration greater than 16 mgriboflavin/100 ml water.
 16. A process for the production of tabletsfrom a riboflavin granulate in accordance with claim 13, which processcomprises pressing the riboflavin granulate at a compression pressure ofabout 500 kp to about 1000 kp.